What is Factor V Deficiency?
Factor V deficiency, sometimes called Owren disease or parahemophilia, is a rare disorder that could be inherited from parents or developed later in life. This condition, discovered by Dr. Paul Owren in Norway in 1943, influences the blood’s ability to clot. Symptoms can vary from minor bleeding, such as from the nose or gums, to severe and potentially life-threatening bleeding. The severity of bleeding often depends on factor V (a protein in your blood that helps blood clot) levels. Yet, some people with very low factor V may still only experience mild bleeding symptoms.
The disease can be divided into mild, moderate, or severe based on the amount of factor V in the blood compared to normal levels. If it’s a mild deficiency, then factor V levels are still at least 10% of normal. Moderate deficiency is when the levels are between 1% and 10%. Severe deficiency means less than 1% of normal levels. Lab tests showing a prolonged prothrombin time (PT – a test used to help diagnose bleeding or clotting disorders) and partial thromboplastin time (aPTT – another test to assess clotting time) could indicate the disease. Factor V deficiency can be confirmed by a low factor V level in the plasma (liquid part of blood).
Further tests, called plasma mixing studies, can differentiate between inherited and acquired factor V deficiency. This involves mixing normal plasma with the patient’s plasma, and examining whether coagulation (clotting) times improve. If clotting times get better, it’s likely an inherited form of the disease where replacing missing factor V can help. If clotting times remain the same, it’s potentially an acquired form, where despite the addition of normal plasma, there is an obstacle preventing proper clotting. However, this test can’t specifically confirm a diagnosis of factor V deficiency.
If someone has inherited factor V deficiency, doctors often provide fresh frozen plasma, which has factor V in it. Mild cases may be treated with drugs named antifibrinolytics to promote blood clotting. On the other hand, managing acquired factor V deficiency needs more advanced treatment. This involves controlling bleeding symptoms and eliminating ‘autoantibodies’, which are antibodies that mistakenly attack and destroy person’s own cells or tissues. Control of bleeding often requires fresh frozen plasma, platelets (which build clots), prothrombin complex concentrates, antifibrinolytics (medications that prevent blood clots from breaking down), or a substance called recombinant activating factor VII. The erring autoantibodies can be removed with the help of immunosuppressive therapies.
Understanding blood clotting: Blood clotting, or coagulation, is orchestrated by a cascade of events across three pathways – intrinsic, extrinsic, and common. When blood vessels get damaged, this triggers a chain reaction to form a clot. This is a crucial mechanism to prevent excessive bleeding. Factor V plays an important role in this, working together with other factors to activate thrombin, a protein that helps in clot formation and stability. Once clotting is achieved, factor V then gets deactivated to prevent excessive clotting.
Factor V also plays a vital part in the anticoagulation pathway, by working in tandem with another protein to de-activate another clotting factor. This ultimately slows down the production of thrombin and fibrin (a protein that forms a clot), hence reducing the formation of clots.
What Causes Factor V Deficiency?
Factor V deficiency can either be genetic (inherited) or develop later in life (acquired). Each type has different causes as explained below.
Inherited Factor V Deficiency
The inherited form of Factor V deficiency is passed down from parents to their children through a pattern known as autosomal recessive. This means that the F5 gene (1q23), which carries mutations related to the disorder, can be passed on in one of two ways. Either both copies of the gene in each cell have mutations (homozygously) or only one copy of the gene in each cell has mutations (heterozygously).
People who carry only one gene mutation (heterozygous carriers) typically do not show symptoms. However, individuals who have mutations in both genes (homozygotes) or two different mutations at the same gene location (compound heterozygotes), may show a range of signs from mild to severe bleeding.
Factor V deficiency is split into Type 1 and Type 2. Type 1 involves a lower amount of Factor V, which is a protein needed for blood clotting, whereas Type 2 involves a reduced function of Factor V, even when its levels are normal or low. More than 190 mutations, or changes to the gene, have been identified, including missense and nonsense mutations, and smaller changes like deletions and insertions.
Symptoms usually start showing before the age of 6. Sometimes, Factor V deficiency can also be inherited along with another deficiency of Factor VIII.
Acquired Factor V Deficiency
The acquired form of Factor V deficiency is less common than the inherited form. It develops due to the production of Factor V inhibitors, which are proteins that interfere with Factor V. Risk factors for this condition include surgery using bovine thrombin (a protein involved in blood clotting), certain antibiotics like β-lactams, cancers, infections, liver disease, and autoimmune disorders (where the body’s immune system accidentally attacks healthy cells). This type of Factor V deficiency has also been found in chronic myelogenous leukemia, a type of cancer that starts in the blood-forming cells of the bone marrow.
Predicting when bleeding episodes will occur can be difficult, as symptoms may not consistently match with the level of Factor V inhibitors, how long the inhibitors have been present, changes in two blood clotting tests (aPTT and PT), or Factor V activity.
Risk Factors and Frequency for Factor V Deficiency
Factor V deficiency is a rare blood clotting disorder that occurs in about 1 in 1 million newborns. It tends to affect all genders uniformly with almost 200 known variations. Anyone from any ethnic group is at risk, but it’s more common in areas where marriages between closely related people are frequent. Recent research located a specific mutation in a family in Taiwan. This condition can be passed down the family tree, typically in an “autosomal recessive” pattern, meaning a child has to inherit a faulty gene from both parents to develop the disorder.
Signs and Symptoms of Factor V Deficiency
Factor V deficiency is a medical condition that can present itself with a variety of bleeding symptoms. It can be either inherited or acquired. Inherited forms usually begin showing symptoms in children below the age of 6, but milder forms might not show any signs until adulthood. Acquired forms can occur at any age and can be more difficult to diagnose. Regardless of the type, the symptoms are indistinguishable from other blood clotting disorders.
- Signs in newborns may include bleeding from the umbilical cord’s stump and nipple, nose bleeding, gum bleeding, and subcutaneous hematomas (collections of blood within tissues). Intracranial hemorrhages, or bleeding within the skull, can also occur and may initially display as an accumulation of fluid within the brain (hydrocephalus) and seizures. These conditions require immediate attention.
- In older children and adults, symptoms often include bleeding from the mucus membranes and soft tissues like ecchymosis (discoloration due to bleeding underneath the skin), easy bruising, petechiae (red or purple spots due to bleeding into the skin), nose bleeds, coughing up blood, vomiting blood, black and tarry stools, joint bleeding, blood in urine, heavy menstruation in women, and prolonged bleeding after surgery or trauma. Serious internal bleeding may also happen and if not caught early can lead to a 15%-20% mortality rate.
The cause of the deficiency can sometimes be identified by learning about your family’s medical history – such as any bleeding disorders – or by assessing recent health events, like surgeries, infections, illnesses, antibiotic use, especially of the β-lactam group, or autoimmune diseases.
Physical examinations are crucial for diagnosis. They are meant to identify if bleeding is external or internal. Speeding heart rate and low blood pressure can be signs of a compromised circulatory system in a patient who is bleeding. Doctors will also look out for signs like bleeding from the mouth or nose, coughing up blood, bruising or petechiae in areas likely to get injured, bleeding in the urinary or reproductive system, vomiting blood, black tarry stools, and neurological symptoms like seizures, altered mental state, or specific neurological deficits. Abdominal tenderness or distension and a bulging anterior fontanelle (soft spot on a baby’s head) can also be signs of the condition. In the worst-cases, patients could become unresponsive, stop breathing or lose their pulse, and would need immediate resuscitation.
Testing for Factor V Deficiency
If your doctor thinks you may have a bleeding problem, they may start by doing lab tests. These tests can help them figure out if you have a disorder involving your blood’s ability to clot. The tests might include clotting tests, tests for specific clotting factors in your blood, tests to screen for inhibitors that can affect clotting, and genetic tests.
Clotting Tests
People with Factor V deficiency, a condition that can lead to bleeding problems, often have longer clotting times when tested with PT (prothrombin time) and aPTT (activated partial thromboplastin time) tests. However, the thrombin time (TT) test is usually normal. These findings don’t confirm Factor V deficiency on their own, though. Extra tests are needed to check other factors (fibrinogen, factor II, and factor X) that can affect clotting. Clotting tests could also be prolonged due to liver disease, which affects the production of clotting factors.
When Factor V deficiency is confirmed, another test is done where the patient’s blood is mixed with normal blood. If the clotting time returns to normal, it suggests Factor V deficiency. If clotting time doesn’t improve, it means there may be an inhibitor present, which can interfere with the clotting process.
Factor Assays
Factor assays are tests that examine the activity levels of specific factors, like Factor V, in the blood. Based on the levels of Factor V activity, the deficiency is categorized as mild (>10%), moderate (1-10%), or severe (<1%). Apart from Factor V, the activity levels of all other factors are also checked to see if any other deficiencies exist, like the combined deficiency of factors V and VIII.
Inhibitor Screening
Screening for inhibitors is done using tests like lupus anticoagulant and ELISA tests. These tests check for substances, like antibodies against β-2 glycoprotein and cardiolipin, which can interfere with the normal clotting process. The Bethesda assay is another test that measures inhibitors against a specific factor, such as Factor V, in the blood.
Molecular Genetic Analysis
Factor V deficiency can also be diagnosed by examining the DNA of white blood cells. Mutations in a gene known as F5, which is located on chromosome 1 and spans 25 parts of the gene called exomes, are checked for. Most of the mutations occur in specific parts called domains A2, C2, and B. Other genes like MCFD2 and LMAN1 can cause combined deficiency of factors V and VIII because they’re associated with moving these clotting factors around in a cell.
Treatment Options for Factor V Deficiency
Treatment for Factor V deficiency, a rare blood clotting disorder, depends on how severe the condition is and what caused it. Some people with a mild form of the condition that they’ve inherited from their parents may be treated with drugs that slow or stop the breakdown of blood clots. For more severe cases, doctors often use something called Fresh Frozen Plasma (FFP) transfusions. FFP is the liquid portion of the blood that contains clotting factors, like Factor V, which help your blood clot. As Factor V supplements aren’t commercially available, FFP is used to raise Factor V levels in the blood. This treatment is generally used during periods of bleeding or before surgical procedures.
If factor V deficiency is acquired, meaning it wasn’t inherited but developed later in life due to certain medical conditions or medications, asymptomatic patients might not need treatment. This is because the inhibitors that block Factor V in the blood are usually temporary. But, those patients who need to undergo surgery or are experiencing heavy bleeding might need a mix of treatments. This can include transfusions of FFP, platelets (tiny blood cells that help your body form clots to stop bleeding), prothrombin complex concentrate (a medicine used to replace clotting factors), and a medicine called recombinant activated factor VII. The latter can help manage bleeding by activating a clotting factor called factor X, skipping the need for Factor V.
Some treatments aim to get rid of the Factor V inhibitors in the body. These include medicines like corticosteroids, cyclophosphamide, and rituximab, which can decrease the production of harmful antibodies in the blood. High-dose intravenous immunoglobulins and a treatment called plasmapheresis, which involves removing and treating the blood before returning it to the body, have also been used to reduce Factor V inhibitors.
What else can Factor V Deficiency be?
Diagnosing conditions related to blood clotting and platelet action can’t be done just based on symptoms. Other diagnostic tests are needed to make a correct diagnosis. Some disorders affect the coagulation cascade, which is the process by which blood forms clots.
Different types of tests can identify various deficiencies in proteins and factors. These include conditions like Hemophilia A, B, and C, which cause difficulties in blood clotting. Hemophilia A is a deficiency in factor VIII, B is a deficiency in factor IX, and C is a deficiency in factor XI. These conditions generally show prolonged aPTT, which is a test that measures how long it takes for your blood to clot. To distinguish these three types from factor V deficiency, doctors measure factor VIII, IX, or XI levels, which should be normal.
Other health issues can cause prolonged PT and aPTT (both tests to measure clotting time), yet a normal TT (another clotting test). They could be due to:
- Deficiencies in factors II or X
- Combined factors V and VIII co-deficiency
- Deficiency in vitamin K-dependent clotting factors like II, VII, IX, X
- Liver disease
- Afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia, which cause prolonged PT and aPTT, but TT is also prolonged in these cases. Patients with these conditions may experience blood clots or bleeding, but many don’t have symptoms.
Von Willebrand disease, the most common inherited bleeding disorder, should also be ruled out. The symptoms can vary, from mild mucosal bleeding in type 1 to severe bleeding like in hemophilia in type 3. Patients may have prolonged or normal aPTT, a normal PT, normal to low platelet count, and normal to low factor VIII levels.
While they’re rare, platelet function defects like Glanzmann Thrombasthenia and Bernard Soulier syndrome should also be considered. These disorders, which result in normal PT and aPTT, indicate problems with platelet adhesion and aggregation that are separate from the coagulation cascade, the process by which blood forms clots.
What to expect with Factor V Deficiency
Both congenital (present at birth) and acquired (developed later in life) deficiencies in factor V, a vital protein for blood clotting, are extremely rare. There isn’t enough information available to predict the long-term outcomes for people affected by this condition. However, it has been observed that up to 21% of people with this deficiency who experience severe bleeding have a risk of mortality.
Possible Complications When Diagnosed with Factor V Deficiency
Complications from Factor V deficiency can start right after a baby is born. One of the most dangerous complications, although it’s especially rare, is something called intracranial hemorrhages. This is a medical term for bleeding inside the skull, and it can be really hard for doctors to identify in newborns. Even worse, it can also be fatal. While it’s less common, there can also be problems with clotting due to factor V causing things like deep vein thrombosis (blood clots in your leg), cerebral infarction (blockage in the brain), and limb gangrene (dead tissue in arm or leg). If there is any suspicion that a child might have Factor V deficiency, early and immediate treatment is very crucial so as to prevent these dangerous complications from happening.
Known complications:
- Begins right after birth
- Intracranial Hemorrhages (Bleeding inside the skull)
- Deep Vein Thrombosis (Blood clots in the leg)
- Cerebral Infarction (Blockage in the brain)
- Limb Gangrene (Dead tissue in arm or leg)
- Potential life-threatening events
Preventing Factor V Deficiency
Upon learning they have factor V deficiency, a rare condition, patients should receive advice and information. It’s particularly important for women who can have children to understand that this condition can be passed down to their children, and that there could be complications during pregnancy and birth. It’s also essential to check if other family members might have inherited the condition. Everyone in the family should learn how to prevent problems and be aware of potential complications before any surgeries. Wearing an alert bracelet can also be very valuable, as it can help medical professionals quickly recognize and respond to serious complications.
The aim of preventing bleeding in patients suffering from acquired factor V deficiency, is handling the root of the problem. This could mean stopping certain medications, or treating other medical conditions that are making the body produce antibodies. It’s sometimes necessary to carefully monitor blood clotting levels and to provide suitable blood products, like FFP, to ensure normal blood clotting and to prevent bleeds. It’s also key to understand that acquired factor V deficiency is often temporary. Regardless, patients should still be very careful to avoid injuries by not engaging in high-risk activities like contact sports.
No matter what caused their condition, people with factor V deficiency must regularly check in with a blood specialist. It’s very important to stay in close contact with healthcare workers especially if there’s a bleeding event.
